Several clinical studies are performed to determine objective and subjective measures associated with smoking and tobacco withdrawal. The results of these studies are applied to develop paradigms for testing of drugs for the treatment of nicotine withdrawal. Neurophysiologic data indicate that nicotine acts on neural substrates involved in attention, cognition and memory. For example, the effects of mecamylamine, a centrally acting nicotinic antagonist is studied to determine the contribution of tonic cholinergic mechanisms on the EEG and cognitive tasks in smokers and nonsmokers. Studies on the effects of smokeless tobacco products, and a newly developed denicotinized cigarette are completed. In an ongoing project, the effects of cigarettes that do not deliver nicotine were compared to placebo cigarettes in a spaced-smoking paradigm. In another study, the effects of the denicotinized cigarettes in a rapid smoking procedure are evaluated. Genetic mechanisms involved in the effect and appeal of cigarette smoking and tobacco withdrawal are investigated. These studies contribute to an understanding of the mechanisms of nicotine addiction and are also of practical value in the development of more effective medications for treating nicotine dependence and withdrawal. Proposed studies include estimating the role of the Nurr1 gene in cigarette smoking behavior. Further studies with alternative tobacco and nicotine delivery products such as hookah smoking are in development. Also being developed is a new test for tobacco exposure by measures of salinisol in cigarette butts.